Characterization of the Biomechanical Heterogeneity of Neurofibromas and Malignant Peripheral Nerve Sheath Tumors

Principal Investigator: MILLS, KRISTEN L
Program: NFRP
Proposal Number: NF180070
Award Number: W81XWH-19-1-0856
Funding Mechanism: New Investigator Award - Early-Stage Investigator
Partnering Awards:
Award Amount: $630,417.00


Neurofibromatosis type I, or NF1, is a genetic disorder affecting 1 in 3000 people. Patients who carry NF1 mutations develop tumors linked to the peripheral nervous system. Neurofibromas are benign tumors either in the skin (dermal/cutaneous) or the surrounding nerves deep in the tissue (plexiform). About 10% of patients with plexiform neurofibromas develop malignant peripheral nerve sheath tumors (MPNSTs). There is no effective treatment course for NF1 patients and a very low life expectancy associated with MPNSTs. Furthermore, despite years of genetic research, the molecular pathway responsible for the transition of a plexiform neurofibroma to an MPNST remains unknown.

An under-researched aspect of NF1 is the role of altered biomechanics in the disease progression. Each kind of tissue in the body has a unique stiffness, which is dictated by its function and is closely linked with the health of the tissue. For example, breast tissue is soft, in part so that specialized muscle cells are able to aid in squeezing milk out of the terminal ends of the milk ducts. Disease, especially solid tumor growth, is sometimes associated with increased stiffness of tissue. For example, breast cancer presents as hard lumps; the increased stiffness is caused by cells that have been damaged due to the disease. Additionally, the increased stiffness promotes increasingly defective behavior in the surrounding cells.

The hypothesis driving the proposed research is that the altered mechanical stiffness in NF1 tumors contributes to their progression as well as the development of MPNSTs. However, measurement of the mechanical stiffness of NF1-associated tumors has not yet been performed, and no correlation of specific defective behaviors of NF1 cells has been made with the resulting altered mechanical stiffness. The proposed work seeks to determine the mechanical stiffness of neurofibromas and MPNSTs and to use that information to generate 3D experimental models to investigate the mechanobiology of NF1 cells and tumor growth.

This research project has the following three experimental aims: (1) to measure the mechanical stiffness of neurofibroma and MPNST tissues from appropriate mouse models of each; (2) to measure the magnitude of forces that NF1 cells impart on materials possessing the measured stiffnesses in aim 1; and (3) to build 3D experimental tumor growth model systems that mimic the properties measured in aims 1 and 2 in order to understand how these properties affect the growth of NF1 tumors.

This new research direction has the short-term goal of identifying the unique mechanical stiffness and mechanical stiffness responses associated with NF1 tumors and NF1 cells, respectively. We will continue to use engineered environments to systematically study the behavior of NF1 tumors and cells with respect to mechanical stiffness. My long-term goal is to identify the molecular pathways responsible for the altered biomechanics associated with tumor development in NF1, thereby opening new avenues for treatment development. In this way, we will identify aspects of NF1 cells to target clinically. Resulting drug treatments should work by (1) blocking the ability of NF1 cells to stiffen the tissue or (2) preventing NF1 cells’ defective behavior in response to the stiffened tissue. Therefore, the tumor burden for NF1 patients would be eased by stalling or reversing the progression.